The long term goal of this project is to define basic molecular mechanisms that underlie circadian rhythms of behavior in vertebrates. A wide variety of biochemical and physiological processes are regulated by circadian clocks, resulting in coordinated daily rhythms of gene expression, metabolism, neurochemical and hormonal functions, and behavior. Disruption of the human circadian system due to disease, aging or voluntary disruption of sleep-wake cycles can lead to diminished sensory and motor performance, sleep disorders or affective disorders. An understanding of the biological basis of circadian rhythmicity will be important for undertanding and treatment of these disorders. The specific goal of this project is to identify and characterize vertebrate genes that are involved in circadian rhythmicity through mutational analysis of the zebrafish circadian system. Recent advances in zebrafish genetics and genomics, together with recently-developed methods for efficient measurement of zebrafish circadian rhythms, make this a useful and economical model system for genetic studies of vertebrate circadian clocks. The specific aims of this project are to: 1) Screen for mutations that affect behavioral circadian rhythms in matugenized zebrafish, recover mutant lines, and characterize the phenotypes of these mutations at the system and cellular levels. 2) Map these mutations on the zebrafish genetic linkage map. 3) Clone and map zebrafish homologs of known circadian clock-related genes and determine whether any of these are disrupted by the newly identified mutations. 4) Use candidate and positional cloning techniques to clone mutated clock genes. This project is expected to result in the identification of novel vertebrate circadian clock genes, and in new information about the functional roles and mechanisms of action of previously- identified clock-related genes.